37 research outputs found

    Sequential Monte Carlo samplers for semilinear inverse problems and application to magnetoencephalography

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    We discuss the use of a recent class of sequential Monte Carlo methods for solving inverse problems characterized by a semi-linear structure, i.e. where the data depend linearly on a subset of variables and nonlinearly on the remaining ones. In this type of problems, under proper Gaussian assumptions one can marginalize the linear variables. This means that the Monte Carlo procedure needs only to be applied to the nonlinear variables, while the linear ones can be treated analytically; as a result, the Monte Carlo variance and/or the computational cost decrease. We use this approach to solve the inverse problem of magnetoencephalography, with a multi-dipole model for the sources. Here, data depend nonlinearly on the number of sources and their locations, and depend linearly on their current vectors. The semi-analytic approach enables us to estimate the number of dipoles and their location from a whole time-series, rather than a single time point, while keeping a low computational cost.Comment: 26 pages, 6 figure

    Bayesian multi--dipole localization and uncertainty quantification from simultaneous EEG and MEG recordings

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    We deal with estimation of multiple dipoles from combined MEG and EEG time--series. We use a sequential Monte Carlo algorithm to characterize the posterior distribution of the number of dipoles and their locations. By considering three test cases, we show that using the combined data the method can localize sources that are not easily (or not at all) visible with either of the two individual data alone. In addition, the posterior distribution from combined data exhibits a lower variance, i.e. lower uncertainty, than the posterior from single device.Comment: 4 pages, 3 figures -- conference paper from EMBEC 2017, Tampere, Finlan

    In-silico modelling of the mitogen-activated protein kinase (MAPK) pathway in colorectal cancer: mutations and targeted therapy

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    Introduction: Chemical reaction networks (CRNs) are powerful tools for describing the complex nature of cancer’s onset, progression, and therapy. The main reason for their effectiveness is in the fact that these networks can be rather naturally encoded as a dynamical system whose asymptotic solution mimics the proteins' concentration profile at equilibrium.Methods and Results: This paper relies on a complex CRN previously designed for modeling colorectal cells in their G1-S transition phase and presents a mathematical method to investigate global and local effects triggered on the network by partial and complete mutations occurring mainly in its mitogen-activated protein kinase (MAPK) pathway. Further, this same approach allowed the in-silico modeling and dosage of a multi-target therapeutic intervention that utilizes MAPK as its molecular target.Discussion: Overall the results shown in this paper demonstrate how the proposed approach can be exploited as a tool for the in-silico comparison and evaluation of different targeted therapies. Future effort will be devoted to refine the model so to incorporate more biologically sound partial mutations and drug combinations

    The Immune-related role of BRAF in melanoma

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    Background: The existence of a dichotomy between immunologically active and quiescent, tumor phenotypes has been recently recognized in several types of cancer. The activation of a Th1 type of immune signature has been shown to confer better prognosis and likelihood to respond to immunotherapy. However, whether such dichotomy depends on the genetic make-up of individual cancers is not known yet. BRAF and NRAS mutations are commonly acquired during melanoma progression. Here we explored the role of BRAF and NRAS mutations in influencing the immune phenotype based on a classification previously identified by our group. Methods: One-hundred-thirteen melanoma metastases underwent microarray analysis and BRAF and NRAS genotyping. Allele-specific PCR was also performed in order to exclude low-frequency mutations. Results: Comparison between BRAF and NRAS mutant versus wild type samples identified mostly constituents or regulators of MAPK and related pathways. When testing gene lists discriminative of BRAF, NRAS and MAPK alterations, we found that 112 BRAF-specific transcripts were able to distinguish the two immune-related phenotypes already described in melanoma, with the poor phenotype associated mostly with BRAF mutation. Noteworthy, such association was stronger in samples displaying low BRAF mRNA expression. However, when testing NRAS mutations, we were not able to find the same association. Conclusion: This study suggests that BRAF mutation-related specific transcripts associate with a poor phenotype in melanoma and provide a nest for further investigation.</br

    Compound heterozygous SCN5A gene mutations in asymptomatic Brugada syndrome child

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    BACKGROUND. Loss-of-function mutations in the SCN5A gene, encoding the cardiac Nav1.5 sodium channel, have been previously associated with Brugada syndrome (BrS). Despite the low prevalence of the disease, we identified a patient carrying two SCN5A mutations. We aimed at establishing a correlation between genotype, clinical phenotype and in vitro sodium current.MATERIALS AND METHODS. A 3 years old boy presented with right bundle branch block and ST-segment elevation. Genetic analysis and electrophysiology studies in transfected HEK293 cells were performed to identify possibly disease-causing variants and assess their effect on sodium channel function.RESULTS. Two SCN5A variants were identified: a new frameshift deletion causing premature truncation of the putative protein (c.3258_3261del4) and a missense substitution (p.F1293S). In vitro studies revealed that the truncated mutant did not produce functional channels and decreased total sodium current when co-expressed with p.F1293S channels compared to p.F1293S alone. In addition, p.F1293S channels presented with a steep slope of steady-state activation voltage-dependency, which was shifted towards more positive potentials by the co-expression with the truncated channel. p.F1293S channels also showed shift towards more positive potentials of the steady-state inactivation both alone and co-expressed with the deletion mutant.CONCLUSIONS. Our data identified a severe reduction of sodium channel current associated with two distinct SCN5A changes. However, all mutation carriers were asymptomatic and BrS ECG was observed only transiently in the compound heterozygous subject. These observations underline the difficulty of genotype/phenotype correlations in BrS patients and support the idea of a polygenic disorder, where different mutations and variants can contribute to the clinical phenotype

    The Matter of Future Heritage

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    In 2018, for the first time, the University of Bologna’s Board of PhD in Architecture and Design Culture assigned second-year PhD students the task of developing and managing an international conference and publishing its works. The organisers of the first edition of this initiative – Giacomo Corda, Pamela Lama, Viviana Lorenzo, Sara Maldina, Lia Marchi, Martina Massari and Giulia Custodi – have chosen to leverage the solid relationship between the Department of Architecture and the Municipality of Bologna to publish a call having to do with the European Year of Cultural Heritage 2018, in which the Municipality was involved. The theme chosen for the call, The Matter of Future Heritage, set itself the ambitious goal of questioning the future of a field of research – Cultural Heritage (CH) – that is constantly being &nbsp;redefined. A work that was made particularly complex in Europe by the development of the H2020 programme, where the topic entered, surprisingly, not as a protagonist but rather as an articulation of other subjects that in the vision of the programme seemed evidently more urgent and, one might say, dominant. The resulting tensions have been considerable and with both negative and positive implications, all the more evident if we refer to the issues that are closest to us namely the city and the landscape

    Longitudinal Study of Recurrent Metastatic Melanoma Cell Lines Underscores the Individuality of Cancer Biology.

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    Recurrent metastatic melanoma provides a unique opportunity to analyze disease evolution in metastatic cancer. Here, we followed up eight patients with an unusually prolonged history of metastatic melanoma, who developed a total of 26 recurrences over several years. Cell lines derived from each metastasis were analyzed by comparative genomic hybridization and global transcript analysis. We observed that conserved, patient-specific characteristics remain stable in recurrent metastatic melanoma even after years and several recurrences. Differences among individual patients exceeded within-patient lesion variability, both at the DNA copy number (P<0.001) and RNA gene expression level (P<0.001). Conserved patient-specific traits included expression of several cancer/testis antigens and the c-kit proto-oncogene throughout multiple recurrences. Interestingly, subsequent recurrences of different patients did not display consistent or convergent changes toward a more aggressive disease phenotype. Finally, sequential recurrences of the same patient did not descend progressively from each other, as irreversible mutations such as homozygous deletions were frequently not inherited from previous metastases. This study suggests that the late evolution of metastatic melanoma, which markedly turns an indolent disease into a lethal phase, is prone to preserve case-specific traits over multiple recurrences and occurs through a series of random events that do not follow a consistent stepwise process.Journal of Investigative Dermatology advance online publication, 2 January 2014; doi:10.1038/jid.2013.495
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